SOLUBILIZATION AND SUSTAINED DELIVERY OF ANTITUMOR AGENT

本研究的总体目标是提供一种新的药物递送 系统，并提高现有化合物的溶解度， 具有优异的抗肿瘤性能，但不溶于水。 含水的 溶解度对于IV给药抗肿瘤药物是必需的。 I期研究将溶解羟基丙二酸二氨铂，2， （反式-1，2-二氨基环己烷）铂羟基丙二酸盐，2，络合物， 将它们与亲水性和可生物降解的聚合物配体缀合， 羧基葡聚糖;以及单体吡喃葡萄糖配体。 配合物1和2 因为它们微溶， 但在水溶液中稳定，并表现出不同的抗肿瘤谱 活性高于顺铂。 这些复合物与羧基葡聚糖的缀合 可以提供抗肿瘤剂持续递送的机制。 结合聚合物或单体配体的优点将被评估 从缀合物的抗肿瘤数据中。 将针对L1210进行新缀合物的初步筛选。 肿瘤 将被ip注射并且治疗将是iv。 选定候选人将 也可以针对一组实体瘤进行筛选。 初步 还将进行肾毒性和肝毒性研究。 该计划的成功将扩大铂络合物的使用范围 在癌症化疗中，这种方法将扩展到 其它不溶性抗肿瘤铂和有机药物在 第二阶段研究。

The overall objective of this study is to provide a new drug delivery system and to enhance the solubility of existing compounds which exhibit excellent antitumor properties but are insoluble in water. Aqueous' solubility is essential for iv administration of antitumor drugs. Phase I research will solubilize diammineplatinumhydroxymalonate, 2, and (trans-1,2-diaminocyclohexane)platinumhydroxymalonate,2, complexes by conjugating them to hydrophilic and biodegradable polymeric ligand, carboxydextran; and to monomeric glucopyranose ligand. Complexes 1 and 2 were selected for solubilization studies because they are sparingly soluble but stable in aqueous solution, and exhibit different spectra of antitumor activity than cisplatin. Conjugation of these complexes to carboxydextran may provide a mechanism for the sustained delivery of antitumor agents. The merits of conjugating polymeric or monomeric ligands will be assessed from the antitumor data of the conjugates. Initial screening of the new conjugates will be done against L1210. Tumor will be injected ip and the treatment will be iv. Selected candidates will also be screened against a panel of solid tumors. Preliminary nephrotoxicity and hepatotoxicity studies will also be undertaken. The success of this program will provide expanded use of platinum complexes in cancer chemotherapy and this approach will be extended to the solubilization of other insoluble antitumor platinum and organic drugs in Phase II research.